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Advances in Drug Research [Vol 26] - B. Testa, U. Meyer (AP, 1995) WW PDF

293 Pages·1995·14.5 MB·English
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ADVANCES IN DRUG RESEARCH VOLUME 26 This Page Intentionally Left Blank ADVANCES IN DRUG RESEARCH Edited by BERNARD TESTA School of Pharmacy, University of Lausanne, Lausanne, Switzerland and URS A. MEYER Institute of Pharmacology, University of Basel, Basel, Switzerland VOLUME 26 ACADEMIC PRESS Harcourt Brace & Company, Publishers LONDON SAN DIEGO NEW YORK BOSTON SYDNEY TOKYO TORONTO This book is printed on acid-free paper ACADEMIC PRESS LIMITED 24-28 Oval Road LONDON NWl 7DX United States Edition published by ACADEMIC PRESS INC. San Diego, CA 92101 Copyright � 9 1995 by ACADEMIC PRESS LIMITED All Rights Reserved No part of this book may be reproduced in any form by photostat, microfilm, or by any other means, without written permission from the publishers A catalogue record for this book is available from the British Library ISBN 0-12-013326-1 Typeset by Keyset Composition, Colchester, Essex Printed and bound in Great Britain by Hartnolls Ltd, Bodmin, Cornwall CONTENTS CONTRIBUTORS . . . . . . . . . . . . . . . . . vii PREFACE . . . . . . . . . . . . . . . . . . . ix Complexity and Emergence in Drug Research L. B. KIER AND B. TESTA 1 General Background . . . . . . . . . . . . . . . 2 2 Some Complex Systems of Interest in Drug Research . . . . 12 3 Applications to Drug Research . . . . . . . . . . . . 26 4 Concluding Remarks . . . . . . . . . . . . . . . 37 References . . . . . . . . . . . . . . . . . . 39 Recommended Reading . . . . . . . . . . . . . . 41 Drug Design: the Present and the Future M. S. TUTE 1 Introduction . . . . . . . . . . . . . . . . . . 46 2 Goals of Design . . . . . . . . . . . . . . . . . 47 3 Methods of Design . . . . . . . . . . . . . . . . 78 4 The Future . . . . . . . . . . . . . . . . . . 131 References . . . . . . . . . . . . . . . . . . 134 Transgenic Animals as Pharmacological Tools K. BISIRKI AND B. LEDERMANN 1 Introduction . . . . . . . . . . . . . . . . . . 144 2 Methods to Generate Genetically Modified Animals . . . . . 147 3 Gain-of-function Models . . . . . . . . . . . . . . 157 4 Loss-of-function Models . . . . . . . . . . . . . . 160 5 Pharmacological Models . . . . . . . . . . . . . . 165 vi CONTENTS 6 Outlook . . . . . . . . . . . . . . . . . . . 170 References . . . . . . . . . . . . . . . . . . 172 Xenobiotic-metabolizing Human Cells as Tools for Pharmacological and Toxocological Research C. L. CRESPI 1 Introduction . . . . . . . . . . . . . . . . . . 180 2 In vitro Systems . . . . . . . . . . . . . . . . . 183 3 General Approaches to cDNA Expression . . . . . . . . 190 4 Challenges . . . . . . . . . . . . . . . . . . 194 5 Criteria for Validation . . . . . . . . . . . . . . . 202 6 State of the Art . . . . . . . . . . . . . . . . . 205 7 Example of Applications . . . . . . . . . . . . . . 220 8 Prospects for the Future . . . . . . . . . . . . . . 228 References . . . . . . . . . . . . . . . . . . 229 Correlates of Variable Patient Compliance in Drug Trials: Relevance in the New Health Care Environment J. URQUHART 1 Introduction . . . . . . . . . . . . . . . . . . 238 2 Overview of Changes in the Health Care Environment . . . . 238 3 Patterns of Misuse and Their Consequences . . . . . . . 241 4 Defining Patient Compliance . . . . . . . . . . . . 242 5 Methodological Advances . . . . . . . . . . . . . 245 6 Compliance Measurement in Clinical Trials . . . . . . . . 246 7 Conclusion . . . . . . . . . . . . . . . . . . 254 References . . . . . . . . . . . . . . . . . . 255 SUBJECT INDEX . . . . . . . . . . . . . . . . . . 259 CUMULATIVE INDEX OF AUTHORS . . . . . . . . . . . . 273 CUMULATIVE INDEX OF TITLES . . . . . . . . . . . . . 277 CONTRIBUTORS K. BORKI, Sandoz Pharma Ltd, Preclinical Research, CH-4002 Basel, Switzerland C. L. CRESPI, GENTEST Corporation, 6 Henshaw Street, Woburn, MA 01801, USA L. B. KIER, Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA B. LEDERMANN, Sandoz Pharma Ltd, Preclinical Research, CH-4002 Basel, Switzerland B. TESTA, School of Pharmacy, University of Lausanne, CH-1015 Lausanne, Switzerland M. S. TUTE, University Chemistry Laboratory, University of Kent, Canterbury, Kent CT2 7NH, UK J. UROUHART, 975 Hamilton Avenue, Palo Alto, CA 94301, USA and Department of Epidemiology, Rijksuniversiteit Limburg, PO Box 616, 6200 MD Maastricht, The Netherlands vii This Page Intentionally Left Blank PREFACE: ADVANCING DRUG RESEARCH Drug research advances at a rate that never fails to amaze scientists who, like ourselves, are mature enough to discern a deep perspective and still fresh enough to experience awe and wonderment. As for drug researchers, they advance in their enterprise by a combination of expertise and creativity. These two statements may seem contradictory. However, they represent two sides of the same coin----drug research as a human endeavour in which scientists take both the part of actor and audience. In particular, writers of scientific reviews play such a dual role, on the one hand, observing and collecting, on the other, constructing and asserting, �9 . . because science consists not simply of a collection of true facts about the world, but is the body of assertions and theories about the world made by people who are called scientists. It consists, in large part, of what scientists say about the world whatever the true state of the world might be (Lewontin, 1993). And when it comes to constructing and asserting, the present volume is rather unique. As will become rapidly apparent to the many faithful readers of Advances in Drug Research, it differs from all previous volumes in that none of the chapters focuses on a specific class of drugs. In other words, the present volume possesses the singular characteristic of containing only general chapters presenting conceptual and/or methodological advances. Such a feature would find justification, were any required, in the pregnant words of the philosopher Mary Midgley: We already have far more facts than we can handle�9 What we need most is to improve our ways of sorting and relating them--to work on the concepts, to philosophize (Midgley, 1991). The book opens with a chapter by Kier and Testa whose subject is drug research as a whole. This is covered in an unconventional and even provocative way by the adoption of a stance few drug researchers will be familiar with, namely that of complexity and emergent properties. Some readers may be astonished by the thesis advocated in this chapter w that the now well-established science of synergetics and complexity allows chemical and pharmacological phenomena to be seen in a new perspective, thereby ix

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